tbuckley/cabot-search huggingface dataset:
BIOL-01. GENERATION AND MULTI-OMICS CHARACTERIZATION OF 203 PEDIATRIC CNS TUMOUR MODELS REVEALS NEW THERAPEUTIC VULNERABILITIES
Authors: Claire Sun, Paul Daniel, Nicole Chew, Hui Shi, Melissa Loi, Sarah Parackal, Mateusz Koptyra, Shazia Adjumain, Monty Panday, Dilru Habarakada, Motahhareh Tourchi, Naama Neeman, Adam Resnick, Chris Jones, Jason Cain, Ron Firestein
Journal: Neuro-Oncology (2023)

Abstract Pediatric Central Nervous System (CNS) tumors are the leading cause of cancer-related death among children. Identifying new targeted therapies necessitates the use of pediatric cancer models that faithfully recapitulate the patient’s disease. However, the generation and characterization of pediatric cancer models has significantly lagged adult cancers, underscoring the urgent need to develop and characterize pediatric CNS models of disease. Herein, we establish a single-site collection of 233 CNS tumour cell lines, representing 14 distinct brain childhood tumor types. We subjected &amp;gt;200 cell lines to multi-omics analyses (DNA-sequencing, RNA-sequencing, DNA methylation, proteomics, phospho-proteomics), and in parallel performed pharmacological and genetic CRISPR-Cas9 loss of function screens to identify pediatric-specific treatment opportunities and biomarkers. Our work provides insight into specific pathway vulnerabilities in molecularly defined pediatric tumor classes and uncovers biomarker-linked therapeutic opportunities of clinical relevance. Cell line data and resources are provided in an open access portal (vicpcc.org.au/dashboard).
METB-11. EXPANSION OF THE PEDIATRIC BRAIN TUMOR ATLAS: AN OPEN SCIENCE EFFORT OF CHILDREN’S BRAIN TUMOR NETWORK, KIDS FIRST DATA RESOURCE AND CHILDHOOD CANCER DATA INITIATIVE
Authors: Mateusz Koptyra, Bailey Farrow, Catherine Sullivan, Noel Coleman, Komal Rathi, Nicholas Van Kuren, Yuankun Zhu, Allison Heath, Stephanie McGrory, Adam Kraya, Yiran Guo, Miguel Brown, Xiaoyan Huang, Meen Chul Kim, Bo Zhang, Brian Ennis, Jo Lynne Rokita, Christopher Friedman, Jennifer Mason, Jena Lilly, Ximena Cuellar, Trang Duros, Thinh Nguyen, Emmett Drake, Zeinab Helili, Beth Frenkel, Gerri Trooskin, Ariana Familiar, Karthik Viswanathan, Christopher Beck, Madison Hollawell, Valerie Baubet, Peter Madsen, Cassie Kline, Tatiana Patton, Kamnaa Arya, Dani Cardona, Ryan Velasco, Mariarita Santi, Phillip B Storm, Adam C Resnick
Journal: Neuro-Oncology (2023)

Abstract Pediatric central nervous system cancers are the leading disease-related cause of death in children and there is urgent need for curative therapeutic strategies for these tumors. To address the urgency, Children’s Brain Tumor Network (CBTN) has advanced an open science model to accelerate the research discovery for pediatric brain tumors. In first phase of Open Pediatric Brain Tumor Atlas (OpenPBTA) effort CBTN together with Pacific Pediatric Neuro-Oncology Consortium (PNOC) and Gabriella Miller Kids First Data Resource Center (KFDRC) created and characterized over 1000 clinically annotated pediatric brain tumors. The second phase of the OpenPBTA, through resource awards and collaboration across KFDRC, the NCI Childhood Cancer Data Initiative (CCDI), Clinical Proteomic Tumor Analysis Consortium (CPTAC), Center for Cancer Research and partnered institutions and foundations has expanded molecular characterization for an additional 1900 pediatric brain tumor patients and their families. This includes the processing and characterization of &amp;gt;8000 specimens across &amp;gt;50 brain tumor diagnoses. This expansion builds off multimodal data including whole genome, RNA, miRNA and methylation sequencing, proteomics, lipidomics and/or metabolomics. Molecular data is linked to longitudinal clinical data, imaging data, histology images, and pathology reports. The data deposition in the cloud-based environment of the NCI’s CCDI and KFDRC to provide near real-time integration, dissemination, processing, and sharing capability. The approach leverages the DRC platform’s cloud-based computational environment through CAVATICA portal shareable pipelines. Data can be explored via PedcBioPortal, a data visualization/analysis application integrating additional public and deposited datasets. This OpenPBTA expansion released with no embargo provides one of the largest deeply characterized cohorts of samples and associated clinical data for &amp;gt;3000 pediatric brain tumor patients. CBTN’s open-science, rapid-release model aims to accelerate pediatric biomarker and drug discovery research and supports clinical trial development on behalf of changing the outcome for kids with brain tumors.
ATRT-07. CLINICAL APPLICABILITY OF C19MC MIRNA DETECTION IN LIQUID BIOPSIES OF ETMR PATIENTS
Authors: Sibylle Madlener, Julia Furtner, Natalia Stepien, Daniel Senfter, Lisa Mayr, Maximilian Zeyda, Leon Gramss, Barbara Aistleitner, Sabine Spiegl-Kreinecker, Elisa Rivelles, Christian Dorfer, Karl Rössler, Thomas Czech, Amedeo A Azizi, Andreas Peyrl, Daniela Lötsch-Gojo, Leonhard Müllauer, Christine Haberler, Irene Slavc, Johannes Gojo
Journal: Neuro-Oncology (2023)

Abstract Embryonal tumor with multilayered rosettes (ETMR) is a distinct central nervous system tumor entity which is characterized by dysregulation of oncogenic micro RNAs (miRNA). In the majority of cases (approx. 90%), tumors are characterized by amplification of the C19MC locus accompanied by a fusion of this locus to the TTYH1 gene. Beside the very young age of the patients, ETMR is a highly aggressive brain tumor with a dismal clinical outcome. About half of the patients relapse within the first 6 months despite intensive therapy. Based on these facts, a more rapid diagnosis as well as more accurate and faster detection of tumor response or tumor relapse would significantly improve the management of these severely affected young patients. Liquid biopsy has emerged as a highly promising tool to enable minimal invasive detection of molecular parameters to facilitate diagnosis and patient monitoring. Here, we developed a miRNA based liquid biopsy tool and performed a comprehensive profiling of the miRNA landscape in 11 ETMR tumor tissues and matching liquid biopsy samples of patients. The screening of the initial liquid biopsy samples (plasma or serum) taken at diagnosis revealed distinctly enriched miRNA levels. Further, we evaluated the use of the miRNA levels as a longitudinal tumor-monitoring tool. We detected decreasing levels after tumor resection and in long-term survivors and vice versa increasing levels in patients with progressive tumor disease. In conclusion, we developed a reliable and fast method with a turnaround time of only 4 hours between blood draw and analysis of the aberrant expressed miRNA in liquid biopsy samples of ETMR patients correlating with the clinical course of the individual patient.
HGG-18. SINGLE CELL RNA-SEQ ANALYSIS OF PEDIATRIC HIGH-GRADE GLIOMA PATIENT SAMPLES IDENTIFIES COMMON GLIAL AND IMMUNE CELL TYPES THAT HELP TO EXPLAIN HETEROGENEITY AND TUMORIGENESIS
Authors: John DeSisto, Andrew Donson, Andrea Griesinger, Rui Fu, Jean Mulcahy Levy, Nicholas Foreman, Rajeev Vibhakar, Adam Green
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Pediatric high-grade gliomas (PHGG) are aggressive, undifferentiated central nervous system (CNS) tumors. PHGG comprises subtypes that differ phenotypically, histologically and by cellular composition. Despite intensive research, overall survival rates have remained for decades around 2% for diffuse midline glioma (DMG) and 20% for non-DMG PHGG. We hypothesized that PHGG’s heterogeneity, a key difficulty in devising therapies, results from functional and lineage differences in tumor cell types. METHODS Using 19 PHGG samples from our institution’s pediatric brain tumor bank, we constructed a single-cell RNA-Seq (scRNA-Seq) dataset that included tumor and immune cells, generated predicted cell types by mapping the scRNA-Seq data onto known cell types, and performed differential gene expression and geneset enrichment analyses. We acquired bulk RNA-Seq and DNA methylation data to characterize overall tumor properties. RESULTS Samples consisted of several principal tumor cell types, including cells with astrocyte characteristics, oligodendrocyte progenitor cell (OPC) characteristics, and cells that expressed OPC markers but had slight enrichment in mesenchymal and inflammatory gene expression (OPC-like/Mes cells). We also found a potential stemlike population that expressed neural stem cell markers. The predicted astrocytes, OPCs and OPC-like/Mes cells differed in their gene expression profiles, pathway enrichment, and tendency to proliferate as assessed from expression of cell cycle genes. A combined microglia/macrophage population, strongly enriched in mesenchymal and inflammatory gene expression, may serve to induce inflammatory gene expression in tumor cells. Key conclusions from the scRNA-Seq analysis were validated using multi-channel immunofluorescence staining. CONCLUSIONS PHGG comprises a small stemlike population and varying proportions of proliferating glial lineage tumor cells. CNS-resident microglia/macrophages may trigger mesenchymal gene expression in PHGG. We will use our results to investigate the roles of PHGG’s diverse tumor cell populations in resistance to radiotherapy and to develop treatments to target individual cell types comprising PHGG.
ATRT-11. DEVELOPMENT OF NOVEL PRECLINICAL MODELS AND THERAPEUTIC STRATEGIES FOR ETMR
Authors: Carolina Cocito, Esteban Uceda Arias-Stella, Xiaohu Zhang, Crystal McKnight, Zina Itkin, Carleen Klumpp-Thomas, Gustavo Alencastro Veiga Cruzeiro, Susan N Chi, David J Pisapia, Mariella G Filbin, Nadia Dahmane, Craig J Thomas, Jeffrey P Greenfield
Journal: Neuro-Oncology (2023)

Abstract Embryonal Tumor with Multilayered Rosettes (ETMR) is a very rare, aggressive pediatric brain tumor with a dismal 5-year overall survival rate. Few genetic aberrations in miRNA clusters and processing machinery have been detected in ETMRs with 90% of ETMR patients having the C19MC amplification. ETMRs show heterogenous histopathological features, including regions of abundant neuropil, hypercellular regions with multilayered rosettes, and papillary structures resembling primitive neuroectoderm. This unique histology, together with the detection of C19MC or DICER alterations, are necessary for diagnosis. The cellular and molecular mechanisms underlying ETMR development is poorly understood, and targeted therapeutics have not been developed due to scarcity of preclinical models. To expand knowledge of ETMR biology and accelerate the design of novel, it is thus essential to develop preclinical models. We have generated a novel patient-derived ETMR cell line from a resected patient tumor sample (CTBP-03A) and created two patient-derived xenograft (PDX) models (CTBP-03A and CBTP-38). We have used these unique patient-derived cell lines to identify mechanisms driving ETMR development and progression. To identify novel therapeutic targets, we conducted high-throughput drug screening (HTDS) utilizing 2480 approved and investigational drugs, against the CBTP-03A cell line. Among the candidate drugs showing an inhibitory effect on CBTP-03, 63 compounds were selected based on their activity, CNS penetration ability, mechanism of action, and bioavailability, if known. The 63 potency-selected hits were screened in an all-versus-all format, totaling 1953 combinations. The rapidity of action of the top choice compounds used as single agent or in double and triple combination was assessed by caspase glow assay. This initial combination screen identified DNA replication stress and FGF signaling as potential new drug combinations for ETMR. We will thus describe the first combinatorial HTDS on two novel ETMR patient-derived cell lines and potential drug combination strategies for the treatment of ETMR.
Correction: Phase I Dose-Escalation Trial of MIW815 (ADU-S100), an Intratumoral STING Agonist, in Patients with Advanced/Metastatic Solid Tumors or Lymphomas
Authors: Funda Meric-Bernstam, Randy F. Sweis, F. Stephen Hodi, Wells A. Messersmith, Robert H.I. Andtbacka, Matthew Ingham, Nancy Lewis, Xinhui Chen, Marc Pelletier, Xueying Chen, Jincheng Wu, Thomas W. Dubensky, Sarah M. McWhirter, Thomas Müller, Nitya Nair, Jason J. Luke
Journal: Clinical Cancer Research (2023)

In the original version of this article (1), author Thomas W. Dubensky is mistakenly omitted from the author list. This error has been corrected in the latest online HTML and PDF versions of the article and the author contributions and disclosures have been updated as necessary. The authors regret this error.
Measurement properties of the patient global assessment numerical rating scale in moderate-to-severe psoriasis
Authors: Ning Yu, Chen Peng, Jing Zhou, Jun Gu, Jinhua Xu, Xia Li, Xinling Bi, Hui Deng, Xin Li, Yangfeng Ding, Yuling Shi
Journal: British Journal of Dermatology (2023)

Abstract Background Patient global assessment (PtGA) has been recommended as one of the core domains in psoriasis clinical trials. Among multiple versions of PtGA, the single-question, 11-point PtGA numeric rating scale (NRS) remains to be validated in patients with plaque psoriasis. Objectives To evaluate the psychometric characteristics of an 11-point PtGA NRS for disease severity in patients with moderate-to-severe plaque psoriasis. Methods Data were analysed from 759 patients with moderate-to-severe psoriasis in the Shanghai Psoriasis Effectiveness Evaluation CoHort (SPEECH), a prospective, multicentre and observational registry assessing the comparative effectiveness and safety of biologics (adalimumab, ustekinumab, secukinumab or ixekizumab), conventional systemic therapies (acitretin or methotrexate) and phototherapy. Results The test–retest reliability of the PtGA NRS showed good agreement (intraclass correlation coefficient range 0.79–0.83). No floor or ceiling effects of PtGA NRS were observed. The PtGA NRS was significantly correlated with the Psoriasis Area and Severity Index (PASI), static Physician Global Assessment (sPGA), body surface area, Dermatology Quality of Life Index (DLQI) and Hospital Anxiety and Depression Scale. Relatively large correlations of PtGA NRS with PASI and the DLQI ‘symptoms and feelings’ domain (all correlations ≥ 0.4 except at baseline) supported convergent validity. The presence of psoriatic arthritis or joint symptoms had no significant association with the PtGA NRS. In multivariate regression analyses, the PtGA NRS at baseline was predicted by age, lesion extent, lesion intensity, patients’ symptoms and feelings, and impact on work or school. The PtGA NRS displayed known-groups validity with the PASI, sPGA and DLQI score bands. The PtGA NRS was responsive to change in PASI and DLQI after treatment. Anchor- and distribution-based approaches supported –3 as the minimal important difference for PtGA NRS. An absolute PtGA NRS ≤ 2 during follow-up was concordant with the state of minimal disease activity based on a 90% reduction in PASI (PASI 90) or PASI 90 plus a DLQI of 0/1. Sensitivity analysis using subgroup comparison and multiple imputation model yielded consistent conclusions. Conclusions The PtGA NRS showed good reliability, validity and responsiveness in patients with psoriasis, and was feasible in clinical trials and daily practice.
A Quantitative Theory for Genomic Offset Statistics
Authors: Clément Gain, Bénédicte Rhoné, Philippe Cubry, Israfel Salazar, Florence Forbes, Yves Vigouroux, Flora Jay, Olivier François
Journal: Molecular Biology and Evolution (2023)

Abstract Genomic offset statistics predict the maladaptation of populations to rapid habitat alteration based on association of genotypes with environmental variation. Despite substantial evidence for empirical validity, genomic offset statistics have well-identified limitations, and lack a theory that would facilitate interpretations of predicted values. Here, we clarified the theoretical relationships between genomic offset statistics and unobserved fitness traits controlled by environmentally selected loci and proposed a geometric measure to predict fitness after rapid change in local environment. The predictions of our theory were verified in computer simulations and in empirical data on African pearl millet (Cenchrus americanus) obtained from a common garden experiment. Our results proposed a unified perspective on genomic offset statistics and provided a theoretical foundation necessary when considering their potential application in conservation management in the face of environmental change.
Errors in Byline and Affiliation
Journal: JAMA Network Open (2023)

Karen L. Schneider, PhD; Elizabeth J. Bell, MPH, PhD; Cindy. K. Zhou, PhD; Grace Yang, MPA, MA; Patricia Lloyd, PhD; Tainya C. Clarke, PhD, MPH; Michael Wilkinson, MPH; Emily E. Myers, MPH; Kandace L. Amend, PhD; John D. Seeger, DrPH, PharmD; Yoganand Chillarige, MPA; Richard A. Forshee, PhD; Azadeh Shoaibi, PhD, MHS; Steven A. Anderson, PhD, MPP; Hui-Lee Wong, PhD
Protein arginine methyltransferase 1 regulates B cell fate after positive selection in the germinal center in mice
Authors: Ludivine C. Litzler, Astrid Zahn, Kiersten L. Dionne, Adrien Sprumont, Silvana R. Ferreira, Michael R.F. Slattery, Stephen P. Methot, Anne-Marie Patenaude, Steven Hébert, Nisha Kabir, Poorani Ganesh Subramani, Seolkyoung Jung, Stéphane Richard, Claudia L. Kleinman, Javier M. Di Noia
Journal: The Journal of Experimental Medicine (2023)

Positively selected germinal center B cells (GCBC) can either resume proliferation and somatic hypermutation or differentiate. The mechanisms dictating these alternative cell fates are incompletely understood. We show that the protein arginine methyltransferase 1 (Prmt1) is upregulated in murine GCBC by Myc and mTORC-dependent signaling after positive selection. Deleting Prmt1 in activated B cells compromises antibody affinity maturation by hampering proliferation and GCBC light zone to dark zone cycling. Prmt1 deficiency also results in enhanced memory B cell generation and plasma cell differentiation, albeit the quality of these cells is compromised by the GCBC defects. We further demonstrate that Prmt1 intrinsically limits plasma cell differentiation, a function co-opted by B cell lymphoma (BCL) cells. Consistently, PRMT1 expression in BCL correlates with poor disease outcome, depends on MYC and mTORC1 activity, is required for cell proliferation, and prevents differentiation. Collectively, these data identify PRMT1 as a determinant of normal and cancerous mature B cell proliferation and differentiation balance.
Thrombin-activated interleukin-1α drives atherogenesis, but also promotes vascular smooth muscle cell proliferation and collagen production
Authors: Laura C Burzynski, Alejandra Morales-Maldonado, Amanda Rodgers, Lauren A Kitt, Melanie Humphry, Nichola Figg, Martin R Bennett, Murray C H Clarke
Journal: Cardiovascular Research (2023)

Abstract Aims Atherosclerosis is driven by multiple processes across multiple body systems. For example, the innate immune system drives both atherogenesis and plaque rupture via inflammation, while coronary artery-occluding thrombi formed by the coagulation system cause myocardial infarction and death. However, the interplay between these systems during atherogenesis is understudied. We recently showed that coagulation and immunity are fundamentally linked by the activation of interleukin-1α (IL-1α) by thrombin, and generated a novel knock-in mouse in which thrombin cannot activate endogenous IL-1α [IL-1α thrombin mutant (IL-1αTM)]. Methods and results Here, we show significantly reduced atherosclerotic plaque formation in IL-1αTM/Apoe−/− mice compared with Apoe−/− and reduced T-cell infiltration. However, IL-1αTM/Apoe−/− plaques have reduced vascular smooth muscle cells, collagen, and fibrous caps, indicative of a more unstable phenotype. Interestingly, the reduced atherogenesis seen with thrombin inhibition was absent in IL-1αTM/Apoe−/− mice, suggesting that thrombin inhibitors can affect atherosclerosis via reduced IL-1α activation. Finally, bone marrow chimeras show that thrombin-activated IL-1α is derived from both vessel wall and myeloid cells. Conclusions Together, we reveal that the atherogenic effect of ongoing coagulation is, in part, mediated via thrombin cleavage of IL-1α. This not only highlights the importance of interplay between systems during disease and the potential for therapeutically targeting IL-1α and/or thrombin, but also forewarns that IL-1 may have a role in plaque stabilization.
Factors Associated With SARS-CoV-2 Infection at a German Medical Congress During the Omicron Wave
Authors: Alaa Din Abdin, Barbara C. Gärtner, Cristian Munteanu, Isabel Weinstein, Birgit Mele, Philip Gass, Berthold Seitz
Journal: JAMA Network Open (2023)

This cross-sectional study assesses factors associated with SARS-CoV-2 infection rates at the 122nd Annual Congress of the German Society of Ophthalmology in 2022, which was held in-person for the first time in 3 years, during the Omicron wave.
Comparison of Work Patterns Between Physicians and Advanced Practice Practitioners in Primary Care and Specialty Practice Settings
Authors: Lisa S. Rotenstein, Nate Apathy, Susan Edgman-Levitan, Bruce Landon
Journal: JAMA Network Open (2023)

Importance Despite the increasing involvement of advanced practice practitioners (APPs; ie, nurse practitioners and physician assistants) in care delivery across specialties, the work patterns of APPs compared with physicians and how they are integrated into care teams have not been well characterized. Objective To characterize differences between physicians and APPs across specialty types related to days with appointments, visit types seen, and time spent using the electronic health record (EHR). Design, Setting, and Participants This nationwide, cross-sectional study used EHR data from physicians and APPs (ie, nurse practitioners and physician assistants) at all US institutions that used Epic Systems’ EHR between January and May 2021. Data analysis was performed from March 2022 to April 2023. Main Outcomes and Measures Appointment scheduling patterns, percentage of new and established and level of evaluation and management (E/M) visits, and EHR use metrics per day and week. Results The sample consisted of 217 924 clinicians across 389 organizations, including 174 939 physicians and 42 985 APPs. Although primary care physicians were more likely than APPs to have more than 3 days per week with appointments (50 921 physicians [79.5%] vs 17 095 APPs [77.9%]), this trend was reversed for medical (38 645 physicians [64.8%] vs 8124 APPs [74.0%]) and surgical (24 155 physicians [47.1%] vs 5198 APPs [51.7%]) specialties. Medical and surgical specialty physicians saw 6.7 and 7.4 percentage points, respectively, more new patient visits than did their APP counterparts, whereas primary care physicians saw 2.8 percentage points fewer new patient visits than did APPs. Physicians saw a greater percentage of level 4 or 5 visits across all specialties. Medical and surgical physicians spent 34.3 and 45.8 fewer minutes per day, respectively, using the EHR than did APPs in their specialties, whereas primary care physicians spent 17.7 minutes per day more. These differences translated to primary care physicians spending 96.3 minutes more per week using the EHR than APPs, whereas medical and surgical physicians spent 149.9 and 140.7 fewer minutes, respectively, than did their APP counterparts. Conclusions and Relevance This cross-sectional, national study of clinicians found significant differences in visit and EHR patterns for physicians compared with APPs across specialty types. By underscoring the different current usage of physicians vs APPs across specialty types, this study helps place into context the work and visit patterns of physicians compared with APPs and serves as a foundation for evaluations of clinical outcomes and quality.